Efruxifermin Shows Strong Promise for Reversing Liver Fibrosis in MASH Patients

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as NASH, affects roughly a third of the global population in its milder fatty liver form and can silently progress to cirrhosis, liver failure, and hepatocellular carcinoma. Despite this enormous disease burden, approved pharmacological treatments have remained scarce. Efruxifermin, a long-acting IgG1 Fc-FGF21 fusion protein administered once weekly, has emerged as a candidate by targeting both the root cause of excessive hepatic fat and the downstream inflammatory and fibrotic cascades that drive disease progression.

This updated meta-analysis systematically searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov through August 2025, identifying 4 eligible RCTs enrolling 419 patients. The analysis extended prior work by incorporating the most recent Phase 2b trial data and adding hepatic fat fraction (HFF) as a key outcome measure — metrics absent from earlier reviews.

On the primary efficacy endpoints, efruxifermin clearly outperformed placebo. It achieved at least one stage of fibrosis improvement without worsening steatohepatitis at a relative risk of 2.18 (95% CI 1.34–3.57, P=0.002), and NASH/MASH resolution with concurrent fibrosis improvement at RR 5.15 (95% CI 1.52–17.47, P=0.009). A ≥2-point NAS score improvement without fibrosis worsening was three times more likely with efruxifermin (RR 3.34, P<0.001). Importantly, the drug also reduced the Enhanced Liver Fibrosis (ELF) score, liver stiffness measurement (LSM), and serum ProC3 levels — all validated non-invasive fibrosis biomarkers.

For hepatic steatosis, results were striking. Efruxifermin increased the proportion of patients achieving ≥30% HFF reduction nearly fivefold (RR 4.69), ≥50% HFF reduction more than 22-fold (RR 22.57), and liver fat normalization 13-fold (RR 13.03) compared to placebo. These effects align with the drug's mechanism of action — FGF21 analogue activity that reduces lipid accumulation in hepatocytes while simultaneously suppressing inflammatory and pro-fibrotic signaling.

However, efruxifermin was associated with significantly higher rates of gastrointestinal adverse events and treatment-related discontinuations compared to placebo, a safety profile consistent with other FGF21 pathway agents. Notably, a Phase 2b trial in compensated cirrhosis (F4 MASH) showed no significant fibrosis reversal at 36 weeks, though potential benefit emerged at 96 weeks — suggesting efficacy may depend on disease stage and duration of treatment. The authors appropriately caution that the overall evidence base remains limited to 4 trials with relatively short follow-up, and that large-scale, multicenter, long-term RCTs are needed to confirm durability and safety across diverse populations.